As the elderly population increases, dementia due to Alzheimer's disease (AD) poses an escalating public health threat. Research suggests that there are multiple pathways that lead to the development and expression of AD. Small vessel cerebrovascular disease, visualized on magnetic resonance imaging (MRI) as white matter hyperintensities (WMH), is common in normal aging and is associated with normal age-related cognitive decline. Emerging evidence, however, suggests that cerebrovascular disease may also play a role in the pathogenesis of AD. Work from our laboratory shows that WMH are increased among those at risk for AD;are more severe among patients with AD;and predict the rate of cognitive decline among those with AD. These initial observations strongly indicate that it is essential to demonstrate that longitudinal progression of WMH is related to cognitive decline and incident AD in order to establish causality. The overall aim of this study is to examine how the progression of small vessel vascular disease contributes to cognitive decline and incident AD. This study interfaces with ongoing follow up of the Washington Heights Inwood Columbia Aging Project (WHICAP;P01 AG07232), a community-based epidemiological study of aging and dementia. Beginning in 2003, MRI scans were acquired on a subset of 717 non-demented elderly participants. The current study seeks to re-evaluate these participants with follow up MRI 6 years after their baseline scans. Advanced MRI analysis techniques will be applied to quantify the degree o f WMH change in major neuroanatomical regions. Cerebral microbleeds, a marker of amyloid angiopathy, will also be quantified to explore their association with WMH.
The aims i nclude: 1. To examine the longitudinal change in regional WMH with cognitive decline and incident AD. 2. To examine whether severity and WMH change accounts for ethnic group differences in incident AD. 3. To examine the association of WMH distribution and lobar microbleeds, a putative marker of cerebral amyloid angiopathy, among patients with AD and controls. Exploratory aims will examine interrelations among WMH, white matter microstructure, hippocampal volume, and cognition. Findings from this study will clarify the role of small vessel vascular disease in the pathogenesis of cognitive aging and AD, will determine if small vessel vascular disease is a source of ethnic group disparities in AD, and will begin to elucidate the mechanism linking vascular disease to AD.

Public Health Relevance

The prevalence of Alzheimer's disease and associated societal and economic burden is rising as the size of the elderly population continues to increase. This project will identify and characterize vascular factors that may contribute to the development and expression of the disease. It will also identify important factors that may account for ethnic-group disparities in Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG034189-04
Application #
8431387
Study Section
Adult Psychopathology and Disorders of Aging Study Section (APDA)
Program Officer
Anderson, Dallas
Project Start
2010-03-15
Project End
2015-02-28
Budget Start
2013-04-15
Budget End
2014-02-28
Support Year
4
Fiscal Year
2013
Total Cost
$383,611
Indirect Cost
$138,461
Name
Columbia University (N.Y.)
Department
Neurology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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Hamilton, Jamie L; Brickman, Adam M; Lang, Rosalyn et al. (2014) Relationship between depressive symptoms and cognition in older, non-demented African Americans. J Int Neuropsychol Soc 20:756-63
Wiegman, Anne F; Meier, Irene B; Schupf, Nicole et al. (2014) Cerebral microbleeds in a multiethnic elderly community: demographic and clinical correlates. J Neurol Sci 345:125-30
Brickman, Adam M; Schupf, Nicole; Manly, Jennifer J et al. (2014) APOE ?4 and risk for Alzheimer's disease: do regionally distributed white matter hyperintensities play a role? Alzheimers Dement 10:619-29
Meier, Irene B; Gu, Yian; Guzaman, Vanessa A et al. (2014) Lobar microbleeds are associated with a decline in executive functioning in older adults. Cerebrovasc Dis 38:377-83
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Zahodne, Laura B; Stern, Yaakov; Manly, Jennifer J (2014) Depressive symptoms precede memory decline, but not vice versa, in non-demented older adults. J Am Geriatr Soc 62:130-4
Vorburger, Robert S; Habeck, Christian G; Narkhede, Atul et al. (2014) Insight from uncertainty: bootstrap-derived diffusion metrics differentially predict memory function among older adults. Brain Struct Funct :
Janicki, S C; Park, N; Cheng, R et al. (2014) Estrogen receptor ? variants affect age at onset of Alzheimer's disease in a multiethnic female cohort. Dement Geriatr Cogn Disord 38:200-13
Tosto, Giuseppe; Zimmerman, Molly E; Carmichael, Owen T et al. (2014) Predicting aggressive decline in mild cognitive impairment: the importance of white matter hyperintensities. JAMA Neurol 71:872-7

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